Activity-Dependent Transcriptional Program in NGN21 Neurons Enriched for Genetic Risk for Brain-Related Disorders

被引：2
|
作者：
Ma, Yixuan [1 ,2 ,3 ,4 ,5 ,8 ]
Bendl, Jaroslav [1 ,2 ,3 ,4 ,5 ]
Hartley, Brigham J. [2 ,4 ,6 ,7 ]
Fullard, John F. [1 ,2 ,3 ,4 ,5 ]
Abdelaal, Rawan [2 ,4 ,6 ,7 ]
Ho, Seok-Man [2 ,4 ,6 ,7 ]
Kosoy, Roman [1 ,2 ,3 ,4 ,5 ]
Gochman, Peter [9 ]
Rapoport, Judith [9 ]
Hoffman, Gabriel E. [1 ,3 ,5 ]
Brennand, Kristen J. [1 ,2 ,4 ,6 ,7 ,12 ,13 ]
Roussos, Panos [1 ,2 ,3 ,4 ,5 ,10 ,11 ]
机构：
[1] Icahn Sch Med Mt Sinai, Ctr Dis Neurogenom, New York, NY 10029 USA
[2] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA
[3] Icahn Sch Med Mt Sinai, Icahn Inst Data Sci & Genom Technol, New York, NY 10029 USA
[4] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA
[5] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
[6] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA
[7] Black Family Stem Cell Inst, New York, NY 10029 USA
[8] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY USA
[9] Natl Inst Mental Hlth, Childhood Psychiat Branch, NIH, Bethesda, MD USA
[10] Nathan S Kline Inst Psychiat Res, Ctr Dementia Res, Orangeburg, NY 10962 USA
[11] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Bronx, NY 10468 USA
[12] Yale Sch Med, Dept Psychiat, New Haven, CT 06510 USA
[13] Yale Sch Med, Dept Genet, New Haven, CT USA
来源：
BIOLOGICAL PSYCHIATRY | 2024年 / 95卷 / 02期
基金：
美国国家卫生研究院;
关键词：
COPY NUMBER VARIANTS; EXPRESSION; STEM; MODEL; DIFFERENTIATION; REGULATORS; NAVIGATOR; CHROMATIN; PROTEINS; SPECTRUM;
D O I：
10.1016/j.biopsych.2023.07.003
中图分类号：
Q189 [神经科学];
学科分类号：
071006 ;
摘要：
BACKGROUND: Converging evidence from large-scale genetic and postmortem studies highlights the role of aberrant neurotransmission and genetic regulation in brain-related disorders. However, identifying neuronal activity-regulated transcriptional programs in the human brain and understanding how changes contribute to disease remain challenging.METHODS: To better understand how the activity-dependent regulome contributes to risk for brain-related disorders, we profiled the transcriptomic and epigenomic changes following neuronal depolarization in human induced pluripotent stem cell-derived glutamatergic neurons (NGN2) from 6 patients with schizophrenia and 5 control participants.RESULTS: Multiomic data integration associated global patterns of chromatin accessibility with gene expression and identified enhancer-promoter interactions in glutamatergic neurons. Within 1 hour of potassium chloride-induced depolarization, independent of diagnosis, glutamatergic neurons displayed substantial activity-dependent changes in the expression of genes regulating synaptic function. Depolarization-induced changes in the regulome revealed significant heritability enrichment for schizophrenia and Parkinson's disease, adding to mounting evidence that sequence variation within activation-dependent regulatory elements contributes to the genetic risk for brain-related disorders. Gene coexpression network analysis elucidated interactions among activity-dependent and diseaseassociated genes and pointed to a key driver (NAV3) that interacted with multiple genes involved in axon guidance. CONCLUSIONS: Overall, we demonstrated that deciphering the activity-dependent regulome in glutamatergic neurons reveals novel targets for advanced diagnosis and therapy.
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页码：187 / 198
页数：12
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